Alteration of mechanical forces is an emerging factor in diseases like cancer. Changes in macroscopic stiffness in disease are accompanied by a wealth of changes in a cell’s tensional homeostasis at a molecular level where mechanotransduction signaling pathways are aberrantly activated. Our lab aims to understand molecular mechanisms utilized by cell-surface receptors to sense and respond to physical stimuli in the cellular environment. I will discuss a new bioluminescence resonance energy transfer (BRET)-based molecular tension sensor that we have developed to help identify mechanosensing proteins in the cell. I will also discuss the molecular mechanisms utilized by the extracellular matrix receptor dystroglycan to regulate proteolysis.